tbuckley/cabot-search huggingface dataset:
Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis
Authors: George Hindy, Daniel J. Tyrrell, Alexi Vasbinder, Changli Wei, Feriel Presswalla, Hui Wang, Pennelope Blakely, Ayse Bilge Ozel, Sarah Graham, Grace H. Holton, Joseph Dowsett, Akl C. Fahed, Kingsley-Michael Amadi, Grace K. Erne, Annika Tekmulla, Anis Ismail, Christopher Launius, Nona Sotoodehnia, James S. Pankow, Lise Wegner Thørner, Christian Erikstrup, Ole Birger Pedersen, Karina Banasik, Søren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, Gunnar Engström, Olle Melander, Marju Orho-Melander, Lili Zhao, Venkatesh L. Murthy, David J. Pinsky, Cristen J. Willer, Susan R. Heckbert, Jochen Reiser, Daniel R. Goldstein, Karl C. Desch, Salim S. Hayek
Journal: Journal of Clinical Investigation (2022)

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin–9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.
Genomics-informed prebreeding unlocks the diversity in genebanks for wheat improvement
Authors: Albert W. Schulthess, Sandip M. Kale, Fang Liu, Yusheng Zhao, Norman Philipp, Maximilian Rembe, Yong Jiang, Ulrike Beukert, Albrecht Serfling, Axel Himmelbach, Jörg Fuchs, Markus Oppermann, Stephan Weise, Philipp H. G. Boeven, Johannes Schacht, C. Friedrich H. Longin, Sonja Kollers, Nina Pfeiffer, Viktor Korzun, Matthias Lange, Uwe Scholz, Nils Stein, Martin Mascher, Jochen C. Reif
Journal: Nature Genetics (2022)
Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea
Authors: Janina Sörmann, Marcus Schewe, Peter Proks, Thibault Jouen-Tachoire, Shanlin Rao, Elena B. Riel, Katherine E. Agre, Amber Begtrup, John Dean, Maria Descartes, Jan Fischer, Alice Gardham, Carrie Lahner, Paul R. Mark, Srikanth Muppidi, Pavel N. Pichurin, Joseph Porrmann, Jens Schallner, Kirstin Smith, Volker Straub, Pradeep Vasudevan, Rebecca Willaert, Elisabeth P. Carpenter, Karin E. J. Rödström, Michael G. Hahn, Thomas Müller, Thomas Baukrowitz, Matthew E. Hurles, Caroline F. Wright, Stephen J. Tucker
Journal: Nature Genetics (2022)

Abstract Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K + channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3 . The mutations cluster around the ‘X-gate’, a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K + channels and their link with sleep apnea but also identify possible therapeutic strategies.
IFITM3 regulates fibrinogen endocytosis and platelet reactivity in nonviral sepsis
Authors: Robert A. Campbell, Bhanu Kanth Manne, Meenakshi Banerjee, Elizabeth A. Middleton, Abigail Ajanel, Hansjorg Schwertz, Frederik Denorme, Chris Stubben, Emilie Montenont, Samantha Saperstein, Lauren Page, Neal D. Tolley, Diana L. Lim, Samuel M. Brown, Colin K. Grissom, Douglas W. Sborov, Anandi Krishnan, Matthew T. Rondina
Journal: Journal of Clinical Investigation (2022)

Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We determined whether nonviral sepsis induces differential platelet gene expression and reactivity. Nonviral sepsis upregulated IFN-induced transmembrane protein 3 (IFITM3), an IFN-responsive gene that restricts viral replication. As IFITM3 has been linked to clathrin-mediated endocytosis, we determined whether IFITM3 promoted endocytosis of α-granule proteins. IFN stimulation enhanced fibrinogen endocytosis in megakaryocytes and platelets from Ifitm+/+ mice, but not Ifitm–/– mice. IFITM3 overexpression or deletion in megakaryocytes demonstrated IFITM3 was necessary and sufficient to regulate fibrinogen endocytosis. Mechanistically, IFITM3 interacted with clathrin and αIIb and altered their plasma membrane localization into lipid rafts. In vivo IFN administration increased fibrinogen endocytosis, platelet reactivity, and thrombosis in an IFITM-dependent manner. In contrast, Ifitm–/– mice were completely rescued from IFN-induced platelet hyperreactivity and thrombosis. During murine sepsis, platelets from Ifitm+/+ mice demonstrated increased fibrinogen content and platelet reactivity, which was dependent on IFN-α and IFITMs. Platelets from patients with nonviral sepsis had increases in platelet IFITM3 expression, fibrinogen content, and hyperreactivity. These data identify IFITM3 as a regulator of platelet endocytosis, hyperreactivity, and thrombosis during inflammatory stress.
Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC
Authors: Laura A. Sena, Rajendra Kumar, David E. Sanin, Elizabeth A. Thompson, D. Marc Rosen, Susan L. Dalrymple, Lizamma Antony, Yuhan Yang, Carolina Gomes-Alexandre, Jessica L. Hicks, Tracy Jones, Kiara A. Bowers, Jillian N. Eskra, Jennifer Meyers, Anuj Gupta, Alyza Skaist, Srinivasan Yegnasubramanian, Jun Luo, W. Nathaniel Brennen, Sushant K. Kachhap, Emmanuel S. Antonarakis, Angelo M. De Marzo, John T. Isaacs, Mark C. Markowski, Samuel R. Denmeade
Journal: Journal of Clinical Investigation (2022)

Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed bipolar androgen therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill defined. Here, we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and were driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pretreatment AR activity predicted downregulation of MYC, improved clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance was overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and resensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.
CD47KO/CRT dual-bioengineered cell membrane-coated nanovaccine combined with anti-PD-L1 antibody for boosting tumor immunotherapy
Authors: Shengyang Liu, Jiayan Wu, Yuanji Feng, Xiaoya Guo, Tong Li, Meng Meng, Jie Chen, Daquan Chen, Huayu Tian
Journal: Bioactive Materials (2022)

Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts' immune systems, and therefore, these vaccines have potential clinical applications. However, the low immunogenicity of the tumor antigen itself and the low efficiency of the vaccine delivery system hinder the efficacy of tumor vaccines that cannot produce high-efficiency and long-lasting antitumor immune effects. Here, we constructed a nanovaccine by integrating CD47KO/CRT dual-bioengineered B16F10 cancer cell membranes and the unmethylated cytosine-phosphate-guanine (CpG) adjuvant. Hyperbranched PEI25k was used to load unmethylated cytosine-phosphate-guanine (CpG) through electrostatic adsorption to prepare PEI25k/CpG nanoparticles (PEI25k/CpG-NPs). CD47KO/CRT dual-bioengineered cells were obtained by CRISPR-Cas9 gene editing technology, followed by the cell surface translocation of calreticulin (CRT) to induce immunogenic cell death (ICD) in vitro. Finally, the extracted cell membranes were coextruded with PEI25k/CpG-NPs to construct the CD47KO/CRT dual-bioengineered cancer cell membrane-coated nanoparticles (DBE@CCNPs). DBE@CCNPs could promote endocytosis of antigens and adjuvants in murine bone marrow derived dendritic cells (BMDCs) and induce their maturation and antigen cross-presentation. To avoid immune checkpoint molecule-induced T cell dysfunction, the immune checkpoint inhibitor, the anti-PD-L1 antibody, was introduced to boost tumor immunotherapy through a combination with the DBE@CCNPs nanovaccine. This combination therapy strategy can significantly alleviate tumor growth and may open up a potential strategy for clinical tumor immunotherapy.
SG Improves OS in HR+/HER2− Breast Cancer
Journal: Cancer Discovery (2022)

The antibody-drug conjugate sacituzumab govitecan, or SG, may be a viable option for patients with metastatic HR-positive/HER2-negative breast cancer who have developed resistance to endocrine drugs. In the phase III TROPiCS-02 trial, compared with standard chemotherapy, SG extended both progression-free and overall survival, besides improving quality of life.
Effects of empagliflozin on cardiovascular and renal outcomes in heart failure with reduced ejection fraction according to age: a secondary analysis of <scp>EMPEROR‐Reduced</scp>
Authors: Gerasimos Filippatos, Stefan D. Anker, Javed Butler, Dimitrios Farmakis, João Pedro Ferreira, Nicholas D. Gollop, Martina Brueckmann, Tomoko Iwata, Stuart Pocock, Faiez Zannad, Milton Packer
Journal: European Journal of Heart Failure (2022)
Positive- and Negative-Pressure Ventilation Characterized by Local and Global Pulmonary Mechanics
Authors: Samaneh Sattari, Crystal A. Mariano, Ware G. Kuschner, Hossein Taheri, Jason H. T. Bates, Mona Eskandari
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

There is continued debate regarding the equivalency of positive-pressure ventilation (PPV) and negative-pressure ventilation (NPV). Resolving this question is important because of the different practical ramifications of the two paradigms.
Exercise‐induced changes in pulmonary artery wedge pressure in adults <scp>post‐Fontan</scp> versus heart failure with preserved ejection fraction and non‐cardiac dyspnoea
Authors: William R. Miranda, Barry A. Borlaug, C. Charles Jain, Jason H. Anderson, Donald J. Hagler, Heidi M. Connolly, Alexander C. Egbe
Journal: European Journal of Heart Failure (2022)
Retraction notice to Noncanonical autophagy in dermal dendritic cells mediates immunosuppressive effects of UV exposure J Allergy Clin Immunol Volume 145, Issue 5, May 2020, Pages 1389-1405
Authors: Payel Sil, Jutamas Suwanpradid, Ginger Muse, Artiom Gruzdev, Liwen Liu, David L. Corcoran, Cynthia J. Willson, Kyathanahalli Janardhan, Sara Grimm, Page Myers, Laura Miller Degraff, Amanda S. MacLeod, Jennifer Martinez
Journal: Journal of Allergy and Clinical Immunology (2022)
Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial
Authors: Donald E. Hricik, Brian Armstrong, Tarek Alhamad, Daniel C. Brennan, Jonathan S. Bromberg, Suphamai Bunnapradist, Sindhu Chandran, Robert. L. Fairchild, David P. Foley, Richard Formica, Ian W. Gibson, Karen Kesler, S. Joseph Kim, Roslyn B. Mannon, Madhav C. Menon, Kenneth A. Newell, Peter Nickerson, Jonah Odim, Emilio D. Poggio, Randall Sung, Ron Shapiro, Kathryn Tinckam, Flavio Vincenti, Peter S. Heeger
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Peritransplant TNF blockade with infliximab should not be used in recipients of deceased-donor kidney transplants due to lack of efficacy and an increased incidence of BK virus infection, according to results of a randomized controlled clinical trial. Our results underscore the need for properly controlled and powered trials to avoid falsely accepting unproven therapeutics and reporting incorrect low adverse event rates derived from small, uncontrolled experiments. Background Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes. Methods We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.2% Black/African American, 44% White) were randomized to receive intravenous infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated before kidney reperfusion. All patients received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary end point was the difference between groups in mean 24-month eGFR. Results There was no difference in the primary end point of 24-month eGFR between IFX (52.45 ml/min per 1.73 m 2 ; 95% CI, 48.38 to 56.52) versus PLBO (57.35 ml/min per 1.73 m 2 ; 95% CI, 53.18 to 61.52; P =0.1). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ, and day 7 post-KTx plasma analyses showed approximately ten-fold lower TNF ( P &lt;0.001) in IFX versus PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) versus PLBO (13.4%; P =0.004), with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) versus PLBO (4.9%; P =0.06). Conclusions IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peritransplant inflammation as a strategy to improve KTx outcomes. Clinical Trial registry name and registration number: clinicaltrials.gov (NCT02495077).
The immune system in multiple myeloma and precursor states: Lessons and implications for immunotherapy and interception
Authors: Madhav V. Dhodapkar
Journal: American Journal of Hematology (2022)

Multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) are distinct disorders that likely originate in the setting of chronic immune activation. Evolution of these lesions is impacted by cross-talk with both innate and adaptive immune systems of the host. Harnessing the immune system may, therefore, be an attractive strategy to prevent clinical malignancy. While clinical MM is characterized by both regional and systemic immune suppression and paresis, immune-based approaches, particularly redirecting T cells have shown remarkable efficacy in MM patients. Optimal application and sequencing of these new immune therapies and their integration into clinical MM management may depend on the underlying immune status, in turn impacted by host, tumor, and environmental features. Immune therapies carry the potential to achieve durable unmaintained responses and cures in MM.
KAGE: fast alignment-free graph-based genotyping of SNPs and short indels
Authors: Ivar Grytten, Knut Dagestad Rand, Geir Kjetil Sandve
Journal: Genome biology (2022)

Abstract Genotyping is a core application of high-throughput sequencing. We present KAGE, a genotyper for SNPs and short indels that is inspired by recent developments within graph-based genome representations and alignment-free methods. KAGE uses a pan-genome representation of the population to efficiently and accurately predict genotypes. Two novel ideas improve both the speed and accuracy: a Bayesian model incorporates genotypes from thousands of individuals to improve prediction accuracy, and a computationally efficient method leverages correlation between variants. We show that the accuracy of KAGE is at par with the best existing alignment-free genotypers, while being an order of magnitude faster.
Time-restricted eating and exercise training improve HbA1c and body composition in women with overweight/obesity: A randomized controlled trial
Authors: Kamilla L. Haganes, Catalina P. Silva, Svala K. Eyjólfsdóttir, Sandra Steen, Martine Grindberg, Stian Lydersen, John A. Hawley, Trine Moholdt
Journal: Cell Metabolism (2022)

Diet modification and exercise training are primary lifestyle strategies for obesity management, but poor adherence rates limit their effectiveness. Time-restricted eating (TRE) and high-intensity interval training (HIIT) improve cardiometabolic health in at-risk individuals, but whether these two interventions combined induce superior improvements in glycemic control than each individual intervention is not known. In this four-armed randomized controlled trial (ClinicalTrials.gov NCT04019860), we determined the isolated and combined effects of 7 weeks of TRE (≤10-h daily eating window, with ad libitum energy intake) and HIIT (three exercise sessions per week), compared with a non-intervention control group, on glycemic control and secondary cardiometabolic outcomes in 131 women (36.2 ± 6.2 years) with overweight/obesity. There were no statistically significant effects after isolated TRE, HIIT, or a combination (TREHIIT) on glucose area under the curve during an oral glucose tolerance test (the primary outcome) compared with the control group (TRE, −26.3 mmol/L; 95% confidence interval [CI], −82.3 to 29.7, p = 0.36; HIIT, −53.8 mmol/L; 95% CI, −109.2 to 1.6, p = 0.057; TREHIIT, −41.3 mmol/L; 95% CI, −96.4 to 13.8, p = 0.14). However, TREHIIT improved HbA1c and induced superior reductions in total and visceral fat mass compared with TRE and HIIT alone. High participant adherence rates suggest that TRE, HIIT, and a combination thereof may be realistic diet-exercise strategies for improving markers of metabolic health in women at risk of cardiometabolic disease.
Focus on diet and exercise
Authors: John Speakman, Alexandra Johnstone, Trine Moholdt, Satchidananda Panda, Samuel Klein, Benjamin L. Parker, Laurie Goodyear
Journal: Cell Metabolism (2022)

Research-based lifestyle choices can help us live healthier lives, and in this issue of Cell Metabolism, we showcase articles focused on diet and exercise interventions. Here, we take a moment to learn about the motivation and challenges behind these studies and look forward to the next steps in applying these interventions to promote metabolic health.
Starving cancer into submission by activating BAT
Authors: Mohammed K. Hankir, Annett Hoffmann, Florian Seyfried
Journal: Cell Metabolism (2022)

Activated brown adipose tissue (BAT) consumes copious amounts of circulating nutrients to fuel thermogenesis. Recently writing in Nature, Seki et al. show that this property can be leveraged to limit glucose availability for cancer cells and slow tumor growth, thereby adding cancer to the growing list of diseases that can potentially be treated by activating BAT. Activated brown adipose tissue (BAT) consumes copious amounts of circulating nutrients to fuel thermogenesis. Recently writing in Nature, Seki et al. show that this property can be leveraged to limit glucose availability for cancer cells and slow tumor growth, thereby adding cancer to the growing list of diseases that can potentially be treated by activating BAT.
Loss of LOXL2 Promotes Uterine Hypertrophy and Tumor Progression by Enhancing H3K36ac-Dependent Gene Expression
Authors: Xufeng Lu, Dazhuan E. Xin, Juanjuan K. Du, Quanli C. Zou, Qian Wu, Yanan S. Zhang, Wenhai Deng, Jicheng Yue, Xing S. Fan, Yuanyuan Zeng, Xiaju Cheng, Xue Li, Zhaoyuan Hou, Man Mohan, Ting C. Zhao, Xiaomei Lu, Zhijie Chang, Liyan Xu, Yu Sun, Xiongbing Zu, Yu Zhang, Y. Eugene Chinn
Journal: Cancer Research (2022)

Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger receptor cysteine-rich (SRCR) repeat carrying LOX family. Although LOXL2 is suspected to be involved in histone association and chromatin modification, the role of LOXL2 in epigenetic regulation during tumorigenesis and cancer progression remains unclear. Here, we report that nuclear LOXL2 associates with histone H3 and catalyzes H3K36ac deacetylation and deacetylimination. Both the N-terminal SRCR repeats and the C-terminal catalytic domain of LOXL2 carry redundant deacetylase catalytic activity. Overexpression of LOXL2 markedly reduced H3K36 acetylation and blocked H3K36ac-dependent transcription of genes, including c-MYC, CCND1, HIF1A, and CD44. Consequently, LOXL2 overexpression reduced cancer cell proliferation in vitro and inhibited xenograft tumor growth in vivo. In contrast, LOXL2 deficiency resulted in increased H3K36 acetylation and aberrant expression of H3K36ac-dependent genes involved in multiple oncogenic signaling pathways. Female LOXL2-deficient mice spontaneously developed uterine hypertrophy and uterine carcinoma. Moreover, silencing LOXL2 in cancer cells enhanced tumor progression and reduced the efficacy of cisplatin and anti-programmed cell death 1 (PD-1) combination therapy. Clinically, low nuclear LOXL2 expression and high H3K36ac levels corresponded to poor prognosis in uterine endometrial carcinoma patients. These results suggest that nuclear LOXL2 restricts cancer development in the female reproductive system via the regulation of H3K36ac deacetylation.LOXL2 loss reprograms the epigenetic landscape to promote uterine cancer initiation and progression and repress the efficacy of anti-PD-1 immunotherapy, indicating that LOXL2 is a tumor suppressor.